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Nature Genetics Dec 2022Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined...
Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined the role of the third most significant chromosomal deletion in human melanoma that inactivates the adherens junction gene NECTIN1 in 55% of cases. We found that NECTIN1 loss stimulates melanoma cell migration in vitro and spreading in vivo in both zebrafish and human tumors specifically in response to decreased IGF1 signaling. In human melanoma biopsy specimens, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study establishes NECTIN1 as a major determinant of melanoma dissemination and uncovers a genetic control of the response to microenvironmental signals.
Topics: Humans; Animals; Zebrafish; Melanoma; Insulin-Like Growth Factor I
PubMed: 36229674
DOI: 10.1038/s41588-022-01191-z -
Frontiers in Endocrinology 2023Cell-cell junctions form strong intercellular connections and mediate communication between blastomeres during preimplantation embryonic development and thus are crucial... (Review)
Review
Cell-cell junctions form strong intercellular connections and mediate communication between blastomeres during preimplantation embryonic development and thus are crucial for cell integrity, polarity, cell fate specification and morphogenesis. Together with cell adhesion molecules and cytoskeletal elements, intercellular junctions orchestrate mechanotransduction, morphokinetics and signaling networks during the development of early embryos. This review focuses on the structure, organization, function and expressional pattern of the cell-cell junction complexes during early embryonic development. Understanding the importance of dynamic junction formation and maturation processes will shed light on the molecular mechanism behind developmental abnormalities of early embryos during the preimplantation period.
Topics: Animals; Female; Pregnancy; Mechanotransduction, Cellular; Intercellular Junctions; Embryonic Development; Morphogenesis; Signal Transduction; Mammals
PubMed: 37152932
DOI: 10.3389/fendo.2023.1150017 -
Current Biology : CB May 2020Cadherin-based cell-cell junctions help metazoans form polarized sheets of cells, which are necessary for the development of organs and the compartmentalization of... (Review)
Review
Cadherin-based cell-cell junctions help metazoans form polarized sheets of cells, which are necessary for the development of organs and the compartmentalization of functions. The components of the protein complexes that generate cadherin-based junctions have ancient origins, with conserved elements shared between animals as diverse as sponges and vertebrates. In invertebrates, the formation and function of epithelial sheets depends on classical cadherin-containing adherens junctions, which link actin to the plasma membrane through α-, β- and p120 catenins. Vertebrates also have a new type of cadherin-based intercellular junction called the desmosome, which allowed for the creation of more complex and effective tissue barriers against environmental stress. While desmosomes have a molecular blueprint that is similar to that of adherens junctions, desmosomal cadherins - called desmogleins and desmocollins - link intermediate filaments (IFs) rather than actin to the plasma membrane through protein complexes comprising relatives of β-catenin (plakoglobin) and p120 catenin (plakophilins). In turn, desmosomal catenins interact with members of the IF-binding plakin family to create the desmosome-IF linking complex. In this Minireview, we discuss when and how desmosomal components evolved, and how their ability to anchor the highly elastic and tough IF cytoskeleton endowed vertebrates with robust tissues capable of not only resisting but also properly responding to environmental stress.
Topics: Animals; Biological Evolution; Desmosomes; Gene Expression Regulation; Membrane Proteins
PubMed: 32428495
DOI: 10.1016/j.cub.2020.03.047 -
Thoracic Cancer Mar 2020Cell junctions serve as a protective barrier for cells and provide an important channel for information transmission between cells and the surrounding environment.... (Review)
Review
Cell junctions serve as a protective barrier for cells and provide an important channel for information transmission between cells and the surrounding environment. Viruses are parasites that invade and commandeer components of host cells in order to survive and replicate, and they have evolved various mechanisms to alter cell junctions to facilitate viral infection. In this review, we examined the current state of knowledge on the action of viruses on host cell junctions. The existing evidence suggests that targeting the molecules involved in the virus-cell junction interaction can prevent the spread of viral diseases.
Topics: Animals; Humans; Intercellular Junctions; Virus Diseases; Viruses
PubMed: 32017415
DOI: 10.1111/1759-7714.13344 -
Open Biology Feb 2020Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication... (Review)
Review
Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication are prerequisites of such cohesive sheets of cells, and cell connectivity is mediated through several junctional assemblies, namely desmosomes, adherens, tight and gap junctions. These cell-cell junctions form signalling hubs that not only mediate cell-cell adhesion but impact on multiple aspects of cell behaviour, helping to coordinate epithelial cell shape, polarity and function. This review will focus on the tight and adherens junctions, constituents of the apical junctional complex, and aims to provide a comprehensive overview of the complex signalling that underlies junction assembly, integrity and plasticity.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Communication; Cell Polarity; Desmosomes; Epithelial Cells; Gap Junctions; Gene Regulatory Networks; Humans; Intercellular Junctions
PubMed: 32070233
DOI: 10.1098/rsob.190278 -
Traffic (Copenhagen, Denmark) Jul 2022E-cadherin has a fundamental role in epithelial tissues by providing cell-cell adhesion. Polarised E-cadherin exocytosis to the lateral plasma membrane is central for...
E-cadherin has a fundamental role in epithelial tissues by providing cell-cell adhesion. Polarised E-cadherin exocytosis to the lateral plasma membrane is central for cell polarity and epithelial homeostasis. Loss of E-cadherin secretion compromises tissue integrity and is a prerequisite for metastasis. Despite this pivotal role of E-cadherin secretion, the transport mechanism is still unknown. Here we identify Myosin V as the motor for E-cadherin secretion. Our data reveal that Myosin V and F-actin are required for the formation of a continuous apicolateral E-cadherin belt, the zonula adherens. We show by live imaging how Myosin V transports E-cadherin vesicles to the plasma membrane, and distinguish two distinct transport tracks: an apical actin network leading to the zonula adherens and parallel actin bundles leading to the basal-most region of the lateral membrane. E-cadherin secretion starts in endosomes, where Rab11 and Sec15 recruit Myosin V for transport to the zonula adherens. We also shed light on the endosomal sorting of E-cadherin by showing how Rab7 and Snx16 cooperate in moving E-cadherin into the Rab11 compartment. Thus, our data help to understand how polarised E-cadherin secretion maintains epithelial architecture and prevents metastasis.
Topics: Actins; Adherens Junctions; Animals; Cadherins; Cell Adhesion; Endosomes; Exocytosis; Humans; Myosin Type V; Neoplasm Metastasis
PubMed: 35575181
DOI: 10.1111/tra.12846 -
International Review of Cell and... 2021Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial... (Review)
Review
Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis development or if it is merely a phenomenon secondary to the aberrant immune response is still unknown. The tight junction complexes are multiprotein cell-cell adhesions that seal the epithelial intercellular space and regulate the paracellular permeability of ions and solutes. These structures have a fundamental role in epithelial barrier integrity as well as in signaling mechanisms that control epithelial-cell polarization, the formation of apical domains and cellular processes such as cell proliferation, migration, differentiation, and survival. In coeliac disease, the molecular structures and function of tight junctions appear disrupted and are not completely recovered after treatment with gluten-free diet. Moreover, zonulin, the only known physiological regulator of the tight junction permeability, appears augmented in autoimmune conditions associated with TJ dysfunction, including coeliac disease. This chapter will examine recent discoveries about the molecular architecture of tight junctions and their functions. We will discuss how different factors contribute to tight junction disruption and intestinal barrier impairment in coeliac disease. To conclude, new insights into zonulin-driven disruption of tight junction structures and barrier integrity in coeliac disease are presented together with the advancements in novel therapy to treat the barrier defect seen in pathogenesis.
Topics: Animals; Celiac Disease; Cell Membrane Permeability; Epithelial Cells; Humans; Immune System; Liver; Tight Junctions
PubMed: 33707052
DOI: 10.1016/bs.ircmb.2020.09.010 -
Science Signaling May 2023Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression...
Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression profile and phenotype. Here, we investigated the role of the transmembrane protein neuropilin-1 (NRP1) in ECs exposed to flow using cultured ECs, mice with an endothelium-specific knockout of NRP1, and a mouse model of atherosclerosis. We demonstrated that NRP1 was a constituent of adherens junctions that interacted with VE-cadherin and promoted its association with p120 catenin, stabilizing adherens junctions and inducing cytoskeletal remodeling in alignment with the direction of flow. We also showed that NRP1 interacted with transforming growth factor-β (TGF-β) receptor II (TGFBR2) and reduced the plasma membrane localization of TGFBR2 and TGF-β signaling. NRP1 knockdown increased the abundance of proinflammatory cytokines and adhesion molecules, resulting in increased leukocyte rolling and atherosclerotic plaque size. These findings describe a role for NRP1 in promoting endothelial function and reveal a mechanism by which NRP1 reduction in ECs may contribute to vascular disease by modulating adherens junction signaling and promoting TGF-β signaling and inflammation.
Topics: Animals; Mice; Adherens Junctions; Endothelial Cells; Endothelium; Neuropilin-1; Receptor, Transforming Growth Factor-beta Type II; Cadherins
PubMed: 37220183
DOI: 10.1126/scisignal.abo4863 -
Cold Spring Harbor Perspectives in... Dec 2022Button-like junctions are discontinuous contacts at the border of oak-leaf-shaped endothelial cells of initial lymphatic vessels. These junctions are distinctively... (Review)
Review
Button-like junctions are discontinuous contacts at the border of oak-leaf-shaped endothelial cells of initial lymphatic vessels. These junctions are distinctively different from continuous zipper-like junctions that create the endothelial barrier in collecting lymphatics and blood vessels. Button junctions are point contacts, spaced about 3 µm apart, that border valve-like openings where fluid and immune cells enter lymphatics. In intestinal villi, openings between button junctions in lacteals also serve as entry routes for chylomicrons. Like zipper junctions that join endothelial cells, buttons consist of adherens junction proteins (VE-cadherin) and tight junction proteins (claudin-5, occludin, and others). Buttons in lymphatics form from zipper junctions during embryonic development, can convert into zippers in disease or after experimental genetic or pharmacological manipulation, and can revert back to buttons with treatment. Multiple signaling pathways and local microenvironmental factors have been found to contribute to button junction plasticity and could serve as therapeutic targets in pathological conditions ranging from pulmonary edema to obesity.
Topics: Humans; Adherens Junctions; Cadherins; Endothelial Cells; Lymphatic Vessels; Occludin; Tight Junctions
PubMed: 35534209
DOI: 10.1101/cshperspect.a041178 -
International Journal of Molecular... Jan 2020The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective... (Review)
Review
The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads to pathological changes such as tissue inflammation, ion imbalance, and cancer. To better understand the consequences of such malfunctions, the junctional nanoarchitecture is of great importance since it remains so far largely unresolved, mainly because of major difficulties in dynamically imaging these structures at sufficient resolution and with molecular precision. The rapid development of super-resolution imaging techniques ranging from structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single molecule localization microscopy (SMLM) has now enabled molecular imaging of biological specimens from cells to tissues with nanometer resolution. Here we summarize these techniques and their application to the dissection of the nanoscale molecular architecture of TJs and AJs. We propose that super-resolution imaging together with advances in genome engineering and functional analyses approaches will create a leap in our understanding of the composition, assembly, and function of TJs and AJs at the nanoscale and, thereby, enable a mechanistic understanding of their dysfunction in disease.
Topics: Adherens Junctions; Endothelial Cells; Humans; Microscopy, Fluorescence; Single Molecule Imaging; Tight Junctions
PubMed: 31979366
DOI: 10.3390/ijms21030744